Collateral effects of antibiotics: adverse effects and drug … · 2009. 6. 24. · 20-06-2009 26th ICC 1 Collateral effects of antibiotics Collateral effects of antibiotics: : adverse

20-06-2009 26th ICC 1

Collateral effects of antibioticsCollateral effects of antibiotics :: adverse effects and drug interactionsadverse effects and drug interactions

Françoise Van Bambeke &

Paul M. Tulkens Unité

de Pharmacologie cellulaire et moléculaire,

Centre de Pharmacie

clinique, Louvain Drug Research Institute,

Université

catholique de Louvain.

<www.facm.ucl.ac.be>

Meet the experts – session 41 – June 20th, 2009

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Back to Back to schoolschool ::

a a littlelittle bit of bit of theorytheory

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What are we speaking about ?

•

Adverse event

: harm in a patient administered a drug, but not necessarily caused by the drug

•

Adverse drug reaction

(abbreviated ADR) : harm directly caused by a drug at normal doses

harm has occured

harm may have occured

•

Side effect:a usually predictable or dose-dependent effect of a drug that is not the principal effect for which the drug was chosenthe side effect may be desirable, undesirable, or inconsequential

Nebeker et al., Ann Intern Med. (2004) 140:795-801

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ADR within collateral effects

medication errors

costs

ADRflora

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How to detect ADR ?

type characteristics interest

clinical trials 5000-10,000 patientscomparison with other drugsused in same indicationsno detection of very rare effects

post-marketing studies

larger number of patientsless controlledpossible detection of rare effects

spontaneous reports to pharmacovigilance systems

no estimation of incidence possiblelargely dependent on GP attention and on number of prescriptions

case - non case studies

estimation of risk for rare ADR

case reports often only source for very rare ADR sensitivity

quantification

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• clinical or microbiological• emergence of resistance

• often rare but serious•

not detected before large-scale usage

• PK issues (tissue accumulation)•

lack of specificity for procaryotic target

How to categorize ADR ?

•

Type

:

Rehan et al., Eur. J. Int. Med. (2009) 20: 3–8

type definition

Aaugmented pharmacologic effects (dose dependent and predictable)

B bizarre effects (or idiosyncratic) (dose independent and unpredictable)

C chronic effects

D delayed effects

E end-of-treatment effects

F failure

of therapy

What about antibiotics ?

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importance of monitoring

often related to unpredictable effects

pregnancy as a CI for most AB classes

How to categorize ADR ?

•

Severity

:

http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm

Serious ADR

death

life-threatening

hospitalization (initial or prolonged)

disability -

significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of liferequires intervention to prevent permanent impairment or damage

congenital anomaly

What about antibiotics ?

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How to categorize ADR ?

•

Relatedness to drug

:

Nebeker et al., Ann Intern Med. (2004) 140:795-801

degree criteria Response to dechallenge

certain plausible time relationship to drug administration cannot be explained by concurrent disease / drugs

clinically plausible

probable likely

reasonable time sequence to drug administration unlikely to be attributed to concurrent disease / drugs

clinically reasonable

possible reasonable time sequence to drug administration could also be explained by concurrent disease / drugs

lacking or unclear

unlikely temporal relationship to drug administration makes a causal relationship improbable other drugs / underlying disease provide plausible explanations

-

need to be critically examined in post-marketing studies

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How to categorize ADR ?

•

Frequency

:

definition frequency

very frequent ≤

1/10

frequent ≤

1/100

not frequent ≤

1/1,000

rare ≤

1/10,000

very rare ≤

1/100,000

Importance of all types of post-marketing surveillance systems

(phase IV)

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Which type of ADR can limit antibiotic use ?

weigh

the benefit-risk

ratio !

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Which type of ADR can limit antibiotic use ?

unsevere

moderate

life – threatening

benefit : depends

on

the severity

of infection

risk : what

shall

you

accept

?

is

an antibiotic really

needed

?

is

a severe

ADR acceptable ?

benefit

rare ADR

>>>

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SafetySafety profile profile of the of the mostmost widelywidely usedused antibioticsantibiotics

Toronto argonaut

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Antibiotics recommended in CAP (outpatients)

Carbonnelle et al., ICC (2009) poster 315

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ADR with antibiotics recommended in CAP (SmPC)Class Most frequent or serious ADRβ-lactams (AMX-CLAV)

•

Anaphylactic reactions •

Clostridium difficile -associated colitis•

Digestive tract: diarrhoea, nausea•

Hepatic toxicity, including hepatitis and cholestatic

jaundice•

CNS : agitation, anxiety, insomnia, confusion, convulsions,

…Macrolides(CLR/AZI)

•

Drug interactions (CYP450) •

Clostridium difficile -associated colitis•

Digestive tract: diarrhoea, nausea, vomiting, abnormal taste•

Hepatic toxicity, including hepatitis and cholestatic

jaundice•

Cardiac toxicity (arrhythmias, TdP)•

CNS: headache, confusion, …Ketolides (TEL)

•

Visual disturbance•

Loss of consciousness•

Respiratory failure in patients with myastenia

gravisTetracyclines •

Anaphylactic

reactions

and allergic

skin reactions•

Clostridium difficile -associated

colitis•

Digestive tract: anorexia, dysphagia, nausea, vomiting, diarrhoea, …•

Esophagitis

and esophageal

ulcerations•

Hepatotoxicity•

Photosensitivity•

Blood cells: hemolytic

anaemia, neutro-/ thrombocytopenia, eosinophilia

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ADR with antibiotics recommended in CAP (SmPC)

Class Most frequent or serious ADRFluoroquinolones(LVX/MXF)

•

Anaphylactic reactions and allergic skin reactions•

Clostridium difficile -associated colitis•

Digestive tract: nausea, diarrhoea•

Musculoskeletal (tendinopathies) and cartilage toxicity•

Prolongation of the QTc

interval and isolated cases of torsade

de pointes•

Hematologic toxicity•

Hepatotoxicity•

CNS effects: headache, insomnia, dizziness, convulsions•

Peripheral neuropathy•

PhotosensitivitySulfamides (SMX/TMP)

• Anaphylactic

reactions

and allergic

skin reactions• Clostridium difficile -associated

colitis• Digestive tract: anorexia, dysphagia, nausea, vomiting, diarrhoea,

…• Blood cells: agranulocytosis, anemia, thrombocytopenia, leukopenia,

neutropenia, hypoprothrombinemia, methemoglobinemia, eosinophilia• Metabolic and Nutritional: hyperkalemia

Carbonnelle et al., ICC (2009) poster 315

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ExamplesExamples :: 2 life2 life--threateningthreatening ADR ADR

criticallycritically examinedexamined by registration by registration authoritiesauthorities

• cardiotoxicity

Toronto City Hall

• hepatotoxicity

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Hepatotoxicity

•

Usually idiosyncratic (can be associated with other allergic reactions). 1

•

Clavulanic acid: genetic deficiency in glutathione S-transferases

? 2

(longer latency period than other antibiotics…)

•

Macrolides: related to reactive metabolites (nitrosoalkanes) that covalently bind to proteins, forming modified antigens (immunoallergic

hepatitis) 3

•

Tetracyclines: related to inhibition of mitochondrial β-oxidation of fatty acids 4

•

Fluoroquinolones: remains anecdotal and unpredictable,1 except for for molecules with substituent-generating reactive intermediates

–

difluoroaniline

(temafloxacin

and trovafloxacin) 5

–

cyclopropylamine

(trovafloxacin; for which co-exposure to lipopolysaccharide

may also be critical) 6

1. Robles & Andrade, Rev Esp Quimioter. (2008) 21:224-332. Lucena et al., Hepatology (2008) 48:588-96.3. Pessayre et al., J Antimicrob Chemother (1985) 16 Suppl A: 181-944. Freneaux et al., Hepatology (1988) 8: 1056-625. Blum et al., Clin Infect Dis (1994) 18: 946-50; Chen et al., N Engl J Med (2000) 342:359-60; Lucena et al., Clin Infect Dis (2000)

30: 400-16. Sun et al., Chem Res Toxicol (2008) 21:711-9; Shaw et al., Toxicol Sci. (2009) 107:270-80

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Hepatotoxicity *

Van Bambeke & Tulkens, Drug Saf. (2009) 32:359-378

Antibiotic population Incidence rate (CI) per 100,000 users reference

fluoroquinolones (w/o moxifloxacin)

Outpatient clinic, Sweden

(1995-2005)0.7 (0.5-1.1) [1]

moxifloxacin Outpatient clinic, Sweden

(1995-2005)0.08 (0.0-0.5) [1]

cotrimoxazole Saskatchewan Health Plan, Canada (1982-1986)

1.0 (0.2-5.7) [2]

erythromycin Saskatchewan Health Plan, Canada (1982-1986)

2.0 (0.7-5.9) [2]

amoxicillin- clavulanic acid

General practice research database, United Kingdom (1991-1992)

22.5 (14.7-34.4) [3]

1. De Valle et al., Aliment Pharmacol Ther (2006) 24:1187-952. Perez et al., Epidemiology (1993) 4: 496-5013. Garcia-Rodriguez et al., Arch Intern Med (1996) 156: 1327-32

* international consensus: AAT/Alk. phos. ratio (hepatocellular: ≥

5; cholestatic: ≤

2 ; mixed: > 2 and < 5)

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Severe hepatotoxicity *

Antibiotic Acute liver failure a Critical event

moxifloxacin 6.6 1.6

levofloxacin 2.1 2.2

trovafloxacin 58 42.9

amoxi-clav 10

clarithromycin 1.0

azithromycin 1.0

telithromycin 23 5.8a Empiric Bayes

Geometric Mean (EBGM) studywww.fda.gov/ohrms/dockets/AC/06/slides/2006-4266s1-01-07-FDA-Brinker.ppt

; presented December 2006 to FDA

Liver failure was defined as "acute or severe liver injury with encephalopathy, liver transplant following acute illness, death in the setting of acute liver injury (hospital. with transaminase

elevation, or hyperbilirubinaemia, or clinical jaundice)"

* FDA reporting rate per 10,000,000 prescriptions (spontaneous reports)

withdrawn from the market

restricted indications

Van Bambeke & Tulkens, Drug Saf. (2009) 32:359-378

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QTc prolongation

50

fluoxetine: 2

sparfloxacin: 15

terfenadine: 46

0 10 20 30 40 msec

erythromycin: 30

clarithromycin: 11-22

moxifloxacin: 6-10

Moxifloxacin is used as a positive control for QTc effect(s) in Phase I studies because it offers a positive signal without risk of clinically meaningful adverse effect !

QTc

prolongation and associated

risk

of Torsade de pointes

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QTc prolongation & torsades de pointes

Owens & Ambrose, Clin. Infect. Dis. (2005) 41:S144-157

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Cardiac toxicity

AntibioticTdP for

10,000,000 prescriptions

moxifloxacin 0 (0-26)

levofloxacin 5.4 (2.9-9.3)

gatifloxacin 27 (12-53)

cefuroxime 0.2 –1

erythromycin 0.7 -1.1

clarithromycin 1.8-3.4

azithromycin 0.6 –1

* FDA reporting rate (spontaneous reports)

not on the market

Van Bambeke & Tulkens, Drug Saf. (2009) 32:359-378

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How How cancan toxicitytoxicity profile affect profile affect antibioticantibiotic usage ?usage ?

• restriction of indications• limitation in treatment

duration

• additional

preregistration

studies

3 3 examplesexamples withwith new new drugsdrugs ……Niagara Falls

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O

O

O

N

OCH3

O

O

CH3

O

OOH

N(CH3)2

CH3

N

CH3

CH3

CH3

CH2CH3

CH3

O

CH3

NN

Absence of cladinose:• stability

in acidic

medium

• no induction ~ MLSBCarbamate:• increased

activity

Lateral chain:• binding

to domain

II

• binding

to methylated

ribosomes •

no recognition by efflux pumps

from

S. pneumoniae• improved

PK profile

Van Bambeke et al., Exp.Op.Pharmacother. (2008) 9:267-283

Telithromycin : a promizing ketolide …

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Telithromycin : a promizing ketolide …

Species and resistance genotype Erythromycin Telithromycin

S. pyogenes (WT)(ermB ind.) (ermB const.) (mef)

0.03>64>64

8

0.080.5 -

1

80.5

S. pneumoniae (WT) (ermB const.)

(mef)

0,03>64

2

0.0080.06

0.125

…for respiratory tract infections

Van Bambeke et al., Exp.Op.Pharmacother. (2008) 9:267-283

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Telithromycin : original indications (SmPC)

Rev. March 2004

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Telithromycin : restriction of indications

http://www.fda.gov/cder/drug/infopage/telithromycin/default.htm Van Bambeke et al., Exp.Op.Pharmacother. (2008) 9:267-283

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Telithromycin : restriction of indications (SmPc)

Rev. March 2004

Rev. February 2007a

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Telithromycin : new warnings (SmPc)

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Linezolid : the first oxazolidinone

Tsuji et al. (2005) In Antimicrobial therapy and vaccines, ed. Yu, 223-42

élongationterminaison elongation factors

70Sinitiationcomplexe50S

30SARNm

initiationfactors fMet-tRNA

peptide

Inhibition of the formation of the initiation complex

X

no • antagonism• cross-resistance

new target

Xchloramphenicolaminoglycosides

macrolides lincosamides

tetracyclines

NO

N

O

F

O

HNH

C CH3

O

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Linezolid : the first oxazolidinone (anti-MRSA)

Falagas et al, Lancet Infect Dis. (2008) 8:53-66

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Falagas et al, Lancet Infect Dis. (2008) 8:53-66

Linezolid : the first oxazolidinone (anti-MRSA)

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Linezolid : avoiding prolonged treatment

Gerson et al., Antimicrob.Ag.Chemother. (2002) 46:2723-6

Thrombocytopenia: 2046 "linezolid" patients versus 2001 "comparator" patients - phase III

treatment

> 15 days!

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Linezolid : avoiding prolonged treatment

Forrest et al, ICAAC (2000) abstract 283

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Bressler et al., Lancet Infect. Dis (2004) 4:528-31

Neuropathy - case reports

treatment

> 28 days!

Linezolid : avoiding prolonged treatment

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Linezolid : avoiding prolonged treatment (SmPC)

Revised July 2008

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XX

telavancin

transpeptidase

transglycosylase

Telavancin : a rapidly bactericidal lipoglycopeptide

Van Bambeke et al., TIPS (2008) 29:124-34

O O

NH

HN

NH

HN

NH

O

HOClO

O

O

O

HOOH

ONHCH3

HN

O

HOOC

OH

CONH2

Cl

O OH

HOHO

OO

H3C

CH3NHHO

OH

HN

NH

PO3H2

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Telavancin : delay to re-submission to EMEA

Stryjewski et al., Clin.Infect.Dis. (2008) 46:1683-93

Phase 3 -

Skin and skin structure infections TLV 10 mg/kg q24h vs VAN 1 g q12h ; 7-14 days

Clinical outcome

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Telavancin : delay to re-submission to EMEA

Stryjewski et al., Clin.Infect.Dis. (2008) 46:1683-93

Safety profile

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Telavancin : delay to re-submission to EMEA

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Drug interactions Drug interactions withwith antibioticsantibiotics

•

increased risk

of ADR

•

decreased exposure

to antibiotic

CN tower, Toronto

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Reduction in antibiotic exposure

A. Cipro 750 mgB. + 850 mg CaCO3C. + 600 mg Al(OH)3

Frost et al, Antimicrob.Ag. Chemother. (1992) 36:830-2

reduction in AUC increased risk of therapeutic failureselection

of resistance

Fluoroquinolones / tetracyclines and cations …!

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Alteration of hepatic metabolism

increased metabolismloss of efficacy

decreased metabolismincreased risk of ADR

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Alteration of other metabolic pathways

HO

HO

NH2

HO

HO

NH2

OH

HONH2

dopamine

noradrenalin

serotonin

SEROTONINERGIC syndrome

Taylor et al., Clin. Infect. Dis (2006) 43:180-7

Mono Amino Oxydase A & B

COOH

linezolid

HO

NH2

tyramineSoja sauceaged

cheese red

winesmoked

meat beer

Association with drugs• synthesis• release• metabolism• reuptake• agonists

of receptors

for neurotransmitters!

5 mg/spoon50 mg/100 g 6 mg/20 cl42 mg/33 cl28 mg/100 g

(< 100 mg de tyramine / meal)

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Increased risk of ADR

Targeting the same organ Competition for transport

• cyclosporin

A• aminoglycosides• vancomycin• amphothericin

B

• foscarnet• …

• NSAID• methotrexate• tenofovir/cidofovir•…

OAT

MRP4

adefovir

Adefovir: drug interactions and nephrotoxicity

Many

anti-infective

agents ! remember

patients at

risk

for HBV …

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NeedNeed more information ? more information ?

Toronto University

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Useful databases: ADR …

http://sideeffects.embl.de

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Useful databases: drug interactions …

http://medicine.iupui.edu/clinpharm/ddis/

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Useful databases: drug interactions …

http://www.drugs.com

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TakeTake home message home message ……

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Take home message …

post-marketing surveillance are neededfor detection of rare/severe ADR

•

careful

examination

of these

cases to define link

with

drug

and associated

risk

factors

safety profile should contribute to define• indications• treatment

duration

• conditions of use and of monitoring

drug interactions are important to take into accountfor :• PK/PD issues and associated

risk

of failure

• increased

risks

of toxicity

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Thank you for your attention

… and have a nice day !